PROJECT SUMMARY There are inherent physical uncertainties with particle therapy (i.e. beam range uncertainty) which have become major factors leading to large margins, thereby unnecessarily exposing additional dose to normal tissues, and forcing clinicians taking overly conservative treatment plans to restrict the dose to tumor or avoiding advantageous beam angles to ensure sparing of critical organs at risk. It is critically important to overcome this impediment in order to dramatically enhance particle therapy outcomes and achieve its full clinical benefits. The goal of this research project is to develop an innovative PET image-based on-line verification of proton therapy for brain cancer treatment instead of the current off-line method in order to directly measure the potential deviation of actual proton beam range from that predicted by the treatment plan before the start of treatment. In this project, we challenge the conventional belief and propose a unique approach of using part of the therapy beams for imaging, thus overcoming the long-standing technical obstacle for achieving the on-line PET imaging method. We will pursue three specific aims to achieve the goal of this project: 1) Develop and evaluate a brain PET capable for desired on-line imaging; 2) Develop and evaluate algorithms and software that will select probing beams for range measurement and enable range-shift compensated beam delivery; 3) Establish and improve the on-line PET based range measurement and adaptive particle therapy. The success of this project will fill a critical technical gap and make the on-line PET based range measurement and adaptive particle therapy clinically practical for the first time. It could shift clinical study with a new image-based particle therapy paradigm, which will significantly improve the particle beam targeting, enable new and better treatment plan, and improve the therapy efficacy and patient care. The outcome of this project will also pave the way to develop similar technology for whole-body on-line PET imaging and adaptive particle therapy applications.